Allergy is thought to arise from maladaptive, Th2-polarized immune responses to ubiquitous, otherwise innocuous environmental proteins. While the proteins so targeted represent a tiny fraction of the proteins humans are exposed to, allergenicity is a quite public phenomenon-the same proteins typically behave as allergens across the human population. Why particular proteins tend to act as allergens in susceptible hosts is a fundamental mechanistic question that has remained largely unanswered. The major house dust mite allergen, Der p 2, has structural homology with MD-2, the lipopolysaccharide (LPS)-binding component of the TLR4 signaling complex. Our data indicate that: (a) Der p 2 has functional homology with MD-2 as well, facilitating signaling through direct interactions with the TLR4 complex, and reconstituting LPS-driven TLR4 signaling in the absence of MD-2; (b) Der p 2 facilitates LPS signaling in primary antigen presenting cells, with or without MD-2 being present; and (c) the in vivo allergenic activity of Der p 2 mirrors its in vitro functional and biochemical activity: Der p 2 efficiently drives airway Th2 inflammation in vivo in a TLR4- dependent manner, retaining this ability in the absence of MD-2. These data suggest that Der p 2 tends to be targeted by adaptive immune responses because of its auto-adjuvant properties. The fact that other members of the MD-2 lipid-binding domain family are major allergens and, more broadly, that more than 50% of defined major allergens are lipid-binding proteins, suggests that intrinsic adjuvant activity by such proteins and their accompanying lipid cargo may have some generality as a mechanism underlying the phenomenon of allergenicity. The fundamental hypothesis underlying this proposal is that biologically important functional mimicry of TLR complex proteins underlies the adjuvanticity and allergenicity of Der p 2 and related ML family proteins. The long-term goal of this research program is to use mechanistic knowledge about molecular pathogenesis to devise novel therapeutic approaches to allergic disease. The studies in this proposal will determine the molecular and cellular mechanisms, and biological consequences, of Der p 2-driven TLR4 signaling in experimental allergic asthma, define the molecular requirements for TLR4 activation by Der p 2, and determine whether other major allergens that are ML domain family members exhibit auto-adjuvanticity and allergenicity based on functional mimicry of the TLR complex.